Native somatostatin is comprised of both a 14-amino acid isoform (somatostatin-14) and a 28-amino acid isoform (somatostatin-28). Heiman, et al., Neuroendocrinology, 45:429-436 (1987). Because of the short half-life of the native somatostatin, various somatostatin analogs have been developed, e.g., for the treatment of acromegaly. Raynor, et al., Molecular Pharmacol. 43:838 (1993). Five distinct somatostatin receptors have been identified and characterized. Hoyer, et al., Naunyn-Schmiedeberg""s Arch. Pharmacol., 350:441 (1994). Somatostatin produces a variety of effects, including modulation of hormone release, e.g., growth hormone, glucagon, insulin, amylin, and neurotransmitter release. Some of these effects have been associated with its binding to a specific somatostatin receptor. For example, the inhibition of growth hormone has been attributed to the somatostatin type-2 receptor (xe2x80x9cSSTR-2xe2x80x9d) (Raynor, et al., Molecular Pharmacol. 43:838 (1993); Lloyd, et al., Am. J. Physiol. 268:G102 (1995)) while the inhibition of insulin has been attributed to the somatostatin type-5 receptor (xe2x80x9cSSTR-5xe2x80x9d) (Coy, et al. 197:366-371 (1993)). The following invention relates to a novel class of somatostatin analogs which are antagonists to somatostatin receptors.
The invention features a compound of the formula: 
wherein
A1 is a D- or L-isomer of an aromatic amino acid, or is deleted;
A2 is a D-isomer selected from the group consisting of Cys, Pen, an aromatic amino acid, or an aliphatic amino acid;
A3 is an aromatic amino acid;
A4 is Trp or D-Trp;
A6 is Thr, Thr(Bzl), Gly, Ser, an Eaa, or an aliphatic amino acid;
A7 is Cys, Pen, or an aromatjkic or an aliphatic amino acid;
A8 is a D- or L-isomer selected from the group consisting of Thr, Ser, an aromatic amino acid, or an aliphatic amino acid;
each of R1 and R2, is, independently, H or substituted (e.g., one to four times) or unsubstituted lower alkyl, aryl, aryl lower alkyl, heterocycle, heterocycle lower alkyl, E1SO2 or E1CO (where E1 is aryl, aryl lower alkyl, heterocycle, or heterocycle lower alkyl), where said substituent is halo, lower alkyl, hydroxy, halo lower alkyl, or hydroxy lower alkyl; and
R3 is OH, NH2, C1-12 alkoxy, or NHxe2x80x94Yxe2x80x94CH2xe2x80x94Z, wherein Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H, or CONH2, or R3, together with the carbonyl group of A8 attached thereto, are reduced to form H, lower alkyl, or hydroxy lower alkyl; provided if A2 is D-Cys or D-Pen, and A7 is Cys or Pen, then a disulfide bond links the sidechains of A2 and A7, and if A1 is D-Phe or p-NO2-Phe; A2 is D-Cys; A3 is Phe or Tyr; A6 is Thr or Val; and A7 is Cys; then A8 is xcex2-Nal.
In one embodiment, A2 is D-Cys, A7 is Cys, and A4 is D-Trp. In a further embodiment, A1 is an L-aromatic amino acid. In still a further embodiment, A1 and A3, independently, is xcex2-Nal, o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A6 is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, xcex2-Ala, Gaba, or Val; and A8 is the D- or L-isomer of Thr, Dip, F5-Phe, p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), Igl, Tyr(Bzl), or xcex2-Nal. In yet still another embodiment, A1 is xcex2-Nal, Npa, Igl, Phe, p-F-Phe, Trp, p-Cl-Phe, or p-CN-Phe; A3 is Tyr, Tyr(I), or Pal; A6 is Val, Tle, Nle, Ile, or Leu; A8 is p-F-Phe, xcex2-Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R1 is H, CH3CO, 4-(2-hydroxyethyl)-1-piperazinylacetyl, or 4-(2-hydroxyethyl)-1-piperizineethanesulfonyl; R2 is H; and R3 is NH2.
In another further embodiment, A1 is a D-aromatic amino acid. In still another further embodiment, A1 is D-xcex2-Nal, D-o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-F5-Phe, D-Trp, D-Dip, D-2-Pal, D-Tyr(Bzl), D-His, D-Igl, D-Tyr(I), D-Bta, D-Bip, D-Npa, or D-Pal; A3 is xcex2-Nal, o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A6 is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, xcex2-Ala, Gaba, or Val; and A8 is the D- or L-isomer of Thr, Dip, F5-Phe, p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), Tyr(Bzl), Igl, or xcex2-Nal. In yet still a further embodiment, A1 is D-xcex2-Nal, D-Npa, D-Igl, D-Phe, D-p-F-Phe, D-Trp, D-p-Cl-Phe, or D-p-CN-Phe; A3 is Tyr, Tyr(I), or Pal; A6 is Val, Tle, Nle, Ile, or Leu; A8 is p-F-Phe, xcex2-Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R1 is H, CH3CO, 4-(2-hydroxyethyl)-1-piperazinylacetyl, or 4-(2-hydroxyethyl)-1-piperizineethanesulfonyl; R2 is H; and R3 is NH2.
In still another further embodiment, A1 is deleted, R1 is substituted or unsubstituted E1CO, and R2 is H. In still a further embodiment, R1 is substituted or unsubstituted E1CO (where E1 is phenyl, xcex2-naphthylmethyl, xcex2-pyridinylmethyl, or 3-indolylmethyl); A3 is xcex2-Nal, o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A6 is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, xcex2-Ala, Gaba, or Val; and A8 is the D- or L-isomer of Thr, Dip, F5-Phe, p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), Igl, Tyr(Bzl), or xcex2-Nal. In yet still a further embodiment, R1 is E1CO (where E1 is 4-hydroxy-phenyl, xcex2-naphthylmethyl, or phenyl); A3 is Tyr, Tyr(I), or Pal; A6 is Val, Tle, Nle, Ile, or Leu; A8 is p-F-Phe, xcex2-Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R3 is NH2.
In yet still a further embodiment, R3, together with the carbonyl group of A8 attached thereto, are reduced to form H, lower alkyl, or hydroxy lower alkyl. In still another further embodiment, A1 is the D- or L-isomer of xcex2-Nal, o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A3 is xcex2-Nal, o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A6 is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, xcex2-Ala, Gaba, or Val; and A8 is the D- or L-isomer of Thr, Dip, F5-Phe, p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), Igl, Tyr(Bzl), or xcex2-Nal. In yet still another further embodiment, A1 is the D- or L-isomer of xcex2-Nal, Phe, p-F-Phe, Trp, p-Cl-Phe, or p-CN-Phe; A3 is Tyr, Tyr(I), or Pal; A6 is Val, Tle, Nle, Ile, or Leu; A8 is p-F-Phe, xcex2-Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R1 is H, CH3CO, 4-(2-hydroxyethyl)-1-piperazinylacetyl, or 4-(2-hydroxyethyl)-1-piperizineethanesulfonyl; R2 is H, and R3, together with the carboxy group of A8 attached thereto, are reduced to form H or CH3OH.
In another embodiment, A2 is a D-aromatic amino acid or a D-aliphatic amino acid, A7 is an aromatic amino acid or an aliphatic amino acid, and A4 is D-Trp. In a further embodiment, A1 is an L-amino acid and A2 is a D-aromatic amino acid. In still a further embodiment, A1, A3, and A7 independently, is xcex2-Nal, o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A2 is D-xcex2-Nal, D-o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-F5-Phe, D-Trp, D-Dip, D-2-Pal, D-Tyr(Bzl), D-His, D-Igl, D-Tyr(I), D-Bta, D-Bip, D-Npa, or D-Pal; A6 is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, xcex2-Ala, Gaba, or Val; and A8 is the D- or L-isomer of Thr, Dip, F5-Phe, p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), Tyr(Bzl), Igl, or xcex2-Nal. In yet still a further embodiment, A1 is xcex2-Nal or Phe, A2 is D-Cpa or D-Phe; A3 is Phe or Tyr; A6 is Abu, Thr, or Val; A7 is Phe; and A8 is Thr; R1 is H, CH3CO, 4-(2-hydroxyethyl)-1-piperazinylacetyl, or 4-(2-hydroxyethyl)-1-piperizineethanesulfonyl; R2 is H; and R3 is NH2.
In another further embodiment, A1 is a D-amino acid and A2 is a D-aromatic amino acid. In still a further embodiment, A1 and A2, independently, is D-xcex2-Nal, D-o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-F5-Phe, D-Trp, D-Dip, D-2-Pal, D-Tyr(Bzl), D-His, D-Igl, D-Tyr(I), D-Bta, D-Bip, D-Npa, or D-Pal; A3 and A7, independently, is xcex2-Nal, o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), F5-Phe, Trp, Dip, 2-Pal, His, Igl, Tyr(I), Bta, Bip, Npa, Tyr(Bzl), or Pal; A6 is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, xcex2-Ala, Gaba, or Val; and A8 is the D- or L-isomer of Thr, Dip, F5-Phe, p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), Igl, Tyr(Bzl), or xcex2-Nal. In yet still a further embodiment, A1 is D-xcex2-Nal or D-Phe; A2 is D-Cpa or D-Phe; A3 is Phe or Tyr; A6 is Thr or Val; A7 is Phe; and A8 is Thr; R1 is H, CH3CO, 4-(2-hydroxyethyl)-1-piperazinylacetyl, or 4-(2-hydroxyethyl)-1-piperizineethanesulfonyl; R2 is H; and R3 is NH2.
Examples of compounds of the present invention include the following:
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 2);
(H) (CH3CO)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 5);
(H)-(4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H)-(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No.3);
(H) (CH3CO)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H)-(4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H)-(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 4);
(H) (CH3CO)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (CH3CO)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
H(CH3CO)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (CH3CO)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2 (Analog No. 6);
(H) (CH3CO)-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2;
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2;
H2-Phe-D-Cys-Pal-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H2-Phe-D-Pen-Tyr-D-Trp-Lys-Val-Pen-xcex2-Nal-NH2; or
H2-Phe-D-Pen-Pal-D-Trp-Lys-Thr-Pen-Thr-NH2;
H2-Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys-Dip-NH2 (Analog No. 10);
H2-F5-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-F5-Phe-NH2 (Analog No. 11);
H2-Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 13);
H2-m-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-m-F-Phe-NH2 (Analog No. 14);
H2-o-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-o-F-Phe-NH2 (Analog No. 15);
H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-F-Phe-NH2 (Analog No. 12);
H2-F5-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-F5-Phe-NH2 (Analog No. 16);
H2-F5-Phe-D-Cys-2-Pal-D-Trp-Lys-Val-Cys-F5-Phe-NH2 (Analog No. 17);
H2-xcex2-Nal-D-Cys-His-D-Trp-Lys-Val-Cys-D-Dip-NH2 (Analog No. 19);
H2-Dip-D-Cys-His-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 20);
H2-Dip-D-Cys-His-D-Trp-Lys-Val-Cys-Dip-NH2 (Analog No. 21);
H2-xcex2-Nal-D-Cys-His-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 22);
H2-Trp-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D-xcex2-Nal-NH2 (Analog No. 24);
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D-xcex2-Nal-NH2 (Analog No. 25);
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-p-F-Phe-NH2 (Analog No. 28);
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Tle-Cys-xcex2-Nal-NH2 (Analog No. 29);
H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 30);
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Nle-Cys-xcex2-Nal-NH2 (Analog No. 31);
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Ile-Cys-xcex2-Nal-NH2 (Analog No. 32);
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Gly-Cys-xcex2-Nal-NH2 (Analog No. 33);
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Ala-Cys-xcex2-Nal-NH2 (Analog No. 34);
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Leu-Cys-xcex2-Nal-NH2 (Analog No. 35);
H2-Bip-D-Cys-Tyr-D-Trp-Lys-Ile-Cys-Bip-NH2 (Analog No. 36);
H2-p-F-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-p-F-Phe-NH2 (Analog No. 38);
H2-Npa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Tyr-NH2 (Analog No. 39);
H2-m-F-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-m-F-Phe-NH2 (Analog No. 40);
H2-o-F-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-o-F-Phe-NH2 (Analog No. 41);
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Dip-NH2 (Analog No. 42);
H2-Cpa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Cpa-NH2 (Analog No. 43);
H2-Igl-D-Cys-Pal-D-Trp-Lys-Val-Cys-Igl-NH2 (Analog No. 44);
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-Dip-NH2 (Analog No. 45);
H2-xcex2-Nal-D-Cys-3-I-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 46);
H2-p-CN-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-CN-Phe-NH2 (Analog No. 47);
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D-Dip-NH2 (Analog No. 48);
H2-xcex2-Nal-D-Cys-Bta-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 49);
H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-xcex2-Nal-NH2 (Analog No. 50);
H2-Bpa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Bpa-NH2 (Analog No. 52);
H2-Iph-D-Cys-Pal-D-Trp-Lys-Val-Cys-Iph-NH2 (Analog No. 53);
H2-Trp-D-Cys-Pal-D-Trp-Lys-Tle-Cys-xcex2-Nal-NH2 (Analog No. 54);
H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 55);
H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-xcex2-Nal-NH2 (Analog No. 56);
H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-p-Cl-Phe-NH2 (Analog No. 57);
H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Cha-Cys-p-Cl-Phe-NH2;
H2-p-Cl-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2;
H2-p-Cl-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
H2-p-Cl-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Tle-Cys-xcex2-Nal-NH2;
H2-p-F-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
H2-p-F-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Tle-Cys-xcex2-Nal-NH2;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2;
H2-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2;
(H) (CH3CO)-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2;
H2-p-NO2-Phe-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-Phe-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Tyr-NH2;
H2-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
H2-xcex2-Nal-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys-xcex2-Nal-NH2;
(H) (4-2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NH2;
H2-D-Phe-D-Pen-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
H2-D-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
H2-D-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 9);
H2-D-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
H2-D-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
H2-D-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H2-D-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H2-D-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D-xcex2-Nal-NH2 (Analog No. 26);
H2-D-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-p-F-Phe-NH2 (Analog No. 27);
H2-D-Bip-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2(Analog No. 37);
H2-D-Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2 (Analog No. 18);
H2-D-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-xcex2-Nal-NH2 (Analog No. 51);
H2-D-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-p-Cl-Phe-NH2 (Analog No. 7);
p-NO2-D-Phe-D-Cys-Pal-D-Trp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NH2;
p-NO2-D-Phe-D-Cys-Tyr(Bzl)-D-Trp-Lys-Val-Cys-Tyr(Bzl)-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-D-Phe-D-Cys-Pal-D-Trp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-D-Phe-D-Cys-Tyr(Bzl)-D-Trp-Lys-Val-Cys-Tyr(Bzl)-NH2;
(H) (3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (3-[2-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (3-[2-naphthyl]propionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (3-[2-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (3-[2-naphthyl]propionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys-xcex2-Nal-NH2;
(H) (3-[2-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (3-[2-naphthyl]propionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;
(H) (3-[2-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (3-[2-naphthyl]propionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;
(H) (3-[p-hydroxyphenyl])-D-Cys-Tyr-D-Trp-Lys-Val-Cys-xcex2-Nal-NH2;
(H) (3-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2;
(H) (3-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
(H) (3-phenylylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-xcex2-Nal-NH2 
(H) (3-phenylylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (CH3CO)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (CH3CO)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (CH3CO)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (CH3CO)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H(CH3CO)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (CH3CO)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (CH3CO)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (CH3CO)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl) ethylamide;
(H) (CH3CO)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
H2-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (CH3CO)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (CH3CO)Phe-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl) ethylamide;
(H) (CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (CH3CO)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R-(2-naphthyl)ethylamide;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R-(2-naphthyl)ethylamide;
H2-xcex2-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
H2-Phe-D-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;
H2-Phe-D-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
H2-Phe-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
H2-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2 (Analog No. 1);
(H) (CH3CO)-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
H2-xcex2-Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;
H2-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;
H2-xcex2-Nal-D-Cpa-Pal-D-Trp-Lys-Thr-Phe-Thr-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cpa-Pal-D-Trp-Lys-Thr-Phe-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cpa-Pal-D-Trp-Lys-Thr-Phe-Thr-NH2;
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cpa-Pal-D-Trp-Lys-Thr-Phe-Thr-NH2;
H2-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-xcex2-Nal-NH2;
(H) (CH3CO)-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-xcex2-Nal-NH2;
(H) (4-(2-hydroxyethyl)-1-piperazinylacetyl)-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-xcex2-Nal-NH2; or
(H) (4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-xcex2-Nal-NH2;
H2-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-xcex2-Nal-NH2 (Analog No. 23);
H2-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
H2-D-xcex2-Nal-D-Cpa-Phe-D-Trp-Lys-Val-Phe-Thr-NH2;
H2-D-xcex2-Nal-D-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;
H2-D-Phe-D-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
H2-D-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2 (Analog No. 8); or
H2-D-xcex2-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-xcex2-Nal-NH2; or a pharmaceutically acceptable salt thereof.
With the exception of the N-terminal amino acid, all abbreviations (e.g., Ala or A2) of amino acids in this disclosure stand for the structure ofxe2x80x94NHxe2x80x94CH(R)xe2x80x94COxe2x80x94, wherein R is a side chain of an amino acid (e.g., CH3 for Ala). For the N-terminal amino acid, the abbreviation stands for the structure of xe2x95x90Nxe2x80x94CH(R)xe2x80x94COxe2x80x94, wherein R is a side chain of an amino acid. Pen, xcex2-Ala, Gaba, Nle, Nva, Pal, F5-Phe, 2,4-dichloro-Phe, Cpa, xcex2-Nal, xcex2-1-Nal, Abu, Dip, 2-Pal, Bip, Npa, Igl, Bta, Tle, Bpa, Iph, Cha, Thr(Bzl), Tyr(Bzl), and Aib are respective abbreviations of the following xcex1-amino acids: penicillamine, 3-aminopropionic acid, 4-aminobutyric acid, norleucine, norvaline, xcex2-[3-pyridyl]-alanine, xcex2-[2,3,4,5,6-pentafluorophenyl]-alanine, xcex2-[2,4-dichlorophenyl]-alanine, xcex2-[4-chlorophenyl]-alanine, xcex2-[2-napthyl]-alanine, xcex2-[1-naphthyl]-alanine; 2-aminobutyric acid, 3,3xe2x80x2-diphenylalanine, xcex2-[2-pyridyl]-alanine, 4,4xe2x80x2-biphenylalanine, p-NO2-phenylalanine, 2-indanylglycine, 3-benzothienylalanine, xcex1-[t-butyl]-glycine, 4-bromo-phenylalanine, 4-iodo-phenylalanine, xcex2-(cyclohexyl)-alanine, O-benzyl-threonine, O-benzyl-tyrosine, and 2-aminoisobutyric acid. Tyr(I) refers to an iodinated tyrosine residue (e.g., 3-I-Tyr, 5-I-Tyr, 3,5-I-Tyr) wherein the iodine may be a radioactive isotope, e.g., I125, I127, or I131. An aliphatic amino acid is an xcex1-amino acid having one or two side chains which, independently, are hydrocarbons, e.g., a straight or branched chain of 1-6 carbons. Examples of aliphatic amino acids include Ala, Aib, Val, Leu, Tle, Ile, Nle, Nva, or Abu. An aromatic amino acid is an xcex1-amino acid the side chain of which has a neutral (e.g., not acidic or basic) aromatic substituent, e.g., a substituted or unsubstituted phenyl, naphthyl, or aromatic heterocycle group (e.g., pyridyl or indolyl). Examples of aromatic amino acids include Phe, p-X-Phe (where X is a halo (e.g., F, Cl, Br, or I), OH, OCH3, CH3, or NO2), o-X-Phe (where X is a halo, OH, OCH3, CH3, or NO2), m-X-Phe (where X is a halo, OH, OCH3, CH3, or NO2), His, Pal, Trp, xcex2-Nal, 2,4-dichloro-Phe, Tyr(I), xcex2-[3,4,5-trifluorophenyl]-alanine, Bta, xcex2-[3-cyanophenyl]-alanine, xcex2-[4-cyanophenyl]-alanine, xcex2-[3,4-difluorophenyl]-alanine, xcex2-[3,5-difluorophenyl]-alanine, xcex2-[2-fluorophenyl]-alanine, xcex2-[4-thiazolyl]-alanine, Bip, Dip, Npa, Igl, Bpa, Iph, homophenylalanine, 2-Pal, xcex2-[4-pyridyl]-alanine, xcex2-[4-thiazolyl]-alanine, xcex2-[2-thiazolyl]-alanine, para-(CF3)-phenylalanine, and F5-Phe. What is meant by an xe2x80x9cEaaxe2x80x9d is an amino acid of the formula xe2x80x94NHxe2x80x94[CH(R)rxe2x80x94COxe2x80x94 (where n is 2-6 and R is H, lower alkyl, or hydroxy lower alkyl). Examples of an Eaa include xcex2-Ala and Gaba.
As used herein, xe2x80x9clower alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having 1-6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, sec-butyl, and the like.
As used herein, xe2x80x9carylxe2x80x9d is intended to include any stable monocyclic, bicyclic, or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl, and the like.
The term xe2x80x9cheterocyclylxe2x80x9d, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic or stable 11-15 membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, and the like.
The term xe2x80x9csubstitutedxe2x80x9d is meant to include the recited chemical group (e.g., lower alkyl, heterocycle, aryl, cycloalkyl, etc.) substituted with one to four of the recited substituents (e.g., halo, hydroxy, lower alkyl, etc.). The substituent may be attached to any atom in the chemical group.
The structure of 4-(2-hydroxyethyl)]-1-piperazinylacetyl and 4-(2-hydroxyethyl)]-1-piperizineethanesulfonyl are, respectively, as follows: 
The compounds of this invention can be provided in the form of pharmaceutically acceptable salts. Acceptable salts include, but are not limited to, acid addition salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate, and stearate. Also within the scope of the present invention, where applicable, are salts formed from bases such as sodium or potassium hydroxide. For further examples of pharmaceutically acceptable salts see, xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci. 66:1 (1977).
Where the amino acid residue is optically active, it is the L-isomer that is intended unless otherwise specified. In the formulae set forth herein, the disulfide bond between the thiol group on the side chain of residue A2 (e.g., Cys, Pen, D-Cys, or D-Pen) and the thiol group on the side chain of residue A7 (e.g., Cys or Pen) is not shown.
The peptides of the invention can be used to promote the release of growth hormone or insulin in a subject (e.g., a mammal such as a human patient). Thus, the peptides are useful in the treatment of physiological conditions in which the promotion of the release of growth hormone or insulin is of benefit. The peptides of the invention can also be used in enhancing wound healing or promoting angiogenesis. Also, peptides of the invention having a Tyr(I) residue can be used to image cells containing somatostatin receptors. Such peptides of the invention can be used either in vivo to detect cells having somatostatin receptors (e.g., cancer cells) or in vitro as a radioligand in a somatostatin receptor binding assay. The peptide of the invention can also be used as vectors to target cells with radioactive isotopes.
A therapeutically effective amount of a peptide of this invention and a pharmaceutically acceptable carrier substance (e.g., magnesium carbonate, lactose, or a phospholipid with which the therapeutic compound can form a micelle) together form a therapeutic composition (e.g., a pill, tablet, capsule, or liquid) for administration (e.g., orally, intravenously, transdermally, pulmonarily, vaginally, subcutaneously, nasally, iontophoretically, or by intratracheally) to a subject in need of the peptide. The pill, tablet, or capsule can be coated with a substance capable of protecting the composition from the gastric acid or intestinal enzymes in the subject""s stomach for a period of time sufficient to allow the composition to pass undigested into the subject""s small intestine. The therapeutic composition can also be in the form of a biodegradable or nonbiodegradable sustained release formulation for subcutaneous or intramuscular administration. See, e.g., U.S. Pat. Nos. 3,773,919 and 4,767,628 and PCT Application No. WO 94/00148. Continuous administration can also be obtained using an implantable or external pump (e.g., INFUSAID(trademark) pump) to administer the therapeutic composition.
The dose of a peptide of the present invention for treating the above-mentioned diseases or disorders varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian. Such an amount of the peptide as determined by the attending physician or veterinarian is referred to herein as a xe2x80x9ctherapeutically effective amount.xe2x80x9d
Also contemplated within the scope of this invention is a peptide covered by the above generic formula for both use in treating diseases or disorders associated with the need to promote the release of growth hormone or insulin, and use in detecting somatostatin receptors, e.g., radioimaging.
Other features and advantages of the present invention will be apparent from the detailed description and from the claims.